by Cindy Sui Tee Aun. / Thesis (M.D.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 159-184). / Table of contents --- p.ii / Signed statement --- p.iv / Abstract --- p.v / List of tables --- p.xi / List of figures --- p.xiii / List of abbreviations --- p.xv / Publications and presentations resulting from the work of the thesis --- p.xviii / Chapter SECTION I --- INTRODUCTION --- p.1 / Chapter Chapter 1 --- Hypothesis and Objective --- p.3 / Review of literature --- p.4 / Research plan --- p.28 / Chapter SECTION II --- METHODS --- p.30 / Chapter Chapter 2 --- Research methods --- p.32 / Equipment --- p.34 / Assay and protein binding of propofol --- p.38 / Pharmacokinetic analysis --- p.42 / Statistical methods --- p.48 / Chapter SECTION III --- INDUCTION OF ANAESTHESIA --- p.52 / Chapter Chapter 3 --- Induction dose requirement / Chapter Chapter 4 --- Influence of propofol dose on haemodynamic changes --- p.68 / Chapter Chapter 5 --- Comparison of cardiovascular effects of propofol and thiopentone --- p.76 / Chapter Chapter 6 --- Single dose pharmacokinetics --- p.91 / Chapter SECTION IV --- MAINTENANCE OF ANAESTHESIA --- p.110 / Chapter Chapter 7 --- Pharmacokinetic-model-controlled infusion of propofol --- p.111 / Chapter SECTION V --- ANAESTHESIA AND RECOVERY --- p.131 / Chapter Chapter 8 --- Comparison of anaesthesia and recovery of four anaesthetic techniques --- p.132 / Chapter SECTION VI --- SUMMARY AND CONCLUSIONS --- p.147 / Chapter Chapter 9 --- Summary --- p.148 / Chapter Chapter 10 --- Conclusions --- p.156 / Chapter SECTION VII --- REFERENCES --- p.159 / Chapter SECTION VIII --- APPENDICES --- p.185 / Chapter A --- Acknowledgements --- p.186 / Chapter B --- Calibration data of propofol --- p.189 / Chapter C --- Patient data tables --- p.191 / Chapter D --- Personal Work --- p.224 / Chapter E --- Ethical Committee Approval Certificates --- p.226

Zugl.: Berlin, Freie Universiẗat, Diss., 2009.

Thesis (M.S.)--University of Florida, 2004. / Typescript. Title from title page of source document. Document formatted into pages; contains 43 pages. Includes Vita. Includes bibliographical references.

Orientadora: Profª. Drª. Elizabeth Milla Tambara / Co-orientador: Prof. Dr. Jorge Eduardo Fouto Matias / Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Clínica Cirúrgica. Defesa: Curitiba, 20/12/2013 / Inclui referências / Resumo: A introdução do propofol (2,6-di-isopropilfenol) como agente sedativo tem transformado a área da sedação para procedimentos endoscópicos. Entretanto, um grande inconveniente da sedação com o uso do propofol é sua alta incidência de dor à injeção. A técnica mais utilizada na redução da dor à injeção do propofol tem sido por meio da associação de outros fármacos. O objetivo deste estudo foi avaliar a repercussão da associação do remifentanil ao propofol sobre a incidência de dor à injeção de propofol, e a sua influência sobre a dose total de propofol necessária para realização de sedação em exames de endoscopia digestiva alta diagnóstica (EDA). Foram avaliados cento e cinco pacientes, que foram submetidos à endoscopia digestiva alta diagnóstica, sendo os pacientes divididos aleatoriamente em três grupos de 35 pacientes. O Grupo Controle foi sedado apenas com o uso de propofol, o Grupo de Estudo 1 foi sedado com uso de remifentanil em dose fixa de 0,2 ?g/kg associado ao propofol. E o Grupo de Estudo 2 foi sedado com o uso de remifentanil em dose fixa de 0,3 ?g/kg associado ao propofol. Foram avaliadas a incidência de dor à injeção de propofol e a dose total de propofol necessária para a realização do exame. A amostra se mostrou bastante similar em relação às variáveis idade, peso, altura, sexo e estado físico. De acordo com a natureza dos dados estudados, procedeu-se ao tratamento estatístico julgado adequado. Utilizou-se o teste de t para comparação, entre os grupos analisados, das médias das variáveis: idade; peso; altura (cm); dose (mg/kg). Foi utilizado o teste ??2 para comparação, entre os grupos analisados, das variáveis: sexo; estado físico, dor à injeção de propofol. O nível de significância adotado foi p<0,05. Houve diferença estatística significativa entre os grupos de estudo e o grupo controle tanto no parâmetro dor à injeção do propofol quanto no parâmetro dose total de propofol utilizada (mg/kg). Entretanto, não houve diferenças estatísticas entre os dois grupos de estudo para estes parâmetros. Conclui-se que o uso do remifentanil nas doses de 0,2 ?g/kg e de 0,3 ?g/kg mostrou-se efetivo tanto sobre o parâmetro redução da dor à injeção de propofol quanto sobre o parâmetro dose total de propofol utilizado. Palavras-chave: Sedação. Endoscopia digestiva alta diagnósticos. Propofol. Remifentanil. / Abstract: The introduction of propofol (2,6-diisopropylphenol) as a sedative agent has been changing the area of sedation for endoscopic procedures. Nonetheless, a significant inconvenience to sedation with propofol is the high incidence of pain on injection. The most used technique for propofol injection pain reduction has been to associate it to other drugs. This study aimed at assessing the effect of associating remifentanil to propofol to reduce pain on injection, and how it might affect the total dose of propofol required for sedation in upper digestive tract endoscopy (UDE) for diagnostic purposes. One hundred and five (105) patients who had been submitted to UDE were studied, randomly divided into three groups with thirty-five (35) patients each. The Control Group was sedated with propofol alone, Group 1 was given remifentanil, at a fixed dose of 0.2 ?g/kg, associated to propofol, and Group 2 was given remifentanil, at a fixed dose of 0.3 ?g/kg, associated to propofol. The incidence of pain on propofol injection and the required dose of propofol for the exam were assessed. The sample has shown to be very similar in regard to the variables age, weight, height, gender and physical status. The statistics were analyzed based on the nature of the data collected and as considered fit. The T-test was used to compare, among the groups studied, the means of these variables: age, weight, height (cm), dose (mg/kg). Test ??2 was used to compare, among the groups, the variables: gender; physical status, pain on propofol injection. The significance level adopted was p<0.05. There was significant statistical difference between the study groups and the control group both concerning the pain on injection parameter and the total propofol dose (mg/kg) used. However, there were no statistical differences between the two study groups for those parameters. In conclusion, using remifentanil at 0.2 ?g/kg and 0.3 ?g/kg doses, was shown to be effective on both the reduction of pain on injection and total propofol dose parameters. Key words: Sedation. Upper digestive endoscopy diagnosis. Propofol. Remifentanil.

No description available.

We recognise consciousness in ourselves and in those around us. Consciousness is the essence of our existence, who and what we are, but we are willing and able to let go of it daily during sleep, which we welcome and associate with rest, recovery and well being, knowing that consciousness will return reliably, when we are ready. Yet we cannot define this thing or process which makes us "us". We do not understand how it is constructed from the activity in our brains, how it is deconstructed by sleep, drugs or disease, or how it can be reconstructed by waking or recovery. Our ignorance renders us reliant on inadequate means of measuring consciousness, dependent on movement for its detection. Propofol is an intravenous anaesthetic drug with the capacity to safely, rapidly and reliably produce sedation and anaesthesia, providing an ideal model of unconsciousness for study. Functional magnetic resonance imaging (fMRI) provides a non-invasive means of measuring activity within the brain. EEG is a convenient broad measure of neuronal activity. This thesis exploits the advantages of each of these techniques, fMRI and EEG, first separately and then together, to link highly informative, spatially specific fMRI observations to convenient, reproducible electrophysiological surface measurements. A safe and reliable model of unconsciousness suitable for fMRI interrogation is first developed and explored. Changes in the spatial extent and interregional correlation of neuronal activity when subjects become unresponsive show that the functional connectivity of the striatum is specifically impaired as perception fails. Disruption of the brain’s internal temporal frame of reference impairs the synthesis of perceptions from their fragments. The second experimental chapter specifically examines the behaviour of sleep oscillations during ultraslow increases and decreases in the depth of sedation with propofol. Functional activity shows that the brain is intensely active despite loss of consciousness and reveals measurable transitions in neuronal activity. Combined simultaneous EEG/FMRI then shows that these transitions reflect stepwise changes in the processing of experience and a shift from externally modulated thalamocortical signaling to an internal dialogue.

Einführung: Die physikalischen Eigenschaften des intravenösen Anästhetikums Propofol (2,6-Diisopropylphenol) erlauben dessen fluoreszenzspektrometrische Detektion. Zur Entwicklung eines direkten Online-Monitorings im optisch dichten Medium Blut wird das Signalverhalten von Propofol im mit Blutprodukten gefüllten Kreislaufsystem untersucht. Material und Methoden: Der kontinuierliche Umsatz von 140,2 ml Probenvolumen im Kreislaufmodell mit integrierter Durchflussquarzküvette bezweckt ein stabiles Fluoreszenzniveau des Messmediums, da Blutprodukte in statischer Versuchsanordnung unter der verwendeten Anregungsstrahlung (UV-C) starken photochemischen Bleichungseffekten ausgesetzt sind. Als Messmedien untersucht werden Gefrorenes Frischplasma (GFP), eine Suspension aus Erythrozytenkonzentrat und GFP (EK + GFP) sowie am Versuchstag gespendetes heparinisiertes Vollblut. Es erfolgt die standardisierte Injektionen von vier Propofolboli, durch die im System Konzentrationen von 35,7 μg/ml bis 3,6 μg/ml entstehen und den klinisch relevanten Wirkspiegeln bei Narkoseeinleitung sowie Narkoseaufrechterhaltung entsprechen. Unter Anregung mit Licht der Wellenlänge 274 nm liefert Propofol ein maximales Signal bei 300 nm. Anhand der in engen zeitlichen Abständen aufgenommen Fluoreszenzspektren werden die Propofoleffekte bei 300 nm im Summationsspektrum des Blut-Propofol-Gemischs analysiert. Ergebnisse: Die Signalanstiege bei 300 nm nach Injektion in das mit GFP bzw. EK + GFP gefüllte Kreislaufsystem sind hochsignifikant für die erzeugten Propofolspiegel von 35,7 μg/ml bis 3,6 μg/ml und weisen eine sehr gute lineare Korrelation von R2 = 0,73 bis zu R2 = 0,99 zwischen Fluoreszenzsignal und Propofolkonzentration auf. Allein für diese Messmedien kann durch den Einsatz des Kreislaufmodells ein ausreichend stabiles Fluoreszenzsignal zum Propofolnachweis erreicht werden. Dem Fluoreszenzanstieg nach Propofolinjektion folgt in allen Messmedien ein über 30 Minuten andauernder Signalabfall, für den nach fluoreszenzspektrometrischer Untersuchung von Schlauchproben des Kreislaufmodells die Adsorption des lipophilen Anästhetikums an Silikon als ein ursächlicher Faktor bestimmt werden kann. Schlussfolgerung: Der direkte konzentrationsabhängige Fluoreszenznachweis von klinisch eingesetzten Propofol-Wirkspiegeln gelingt allein in transfusionsmedizinisch aufbreiteten Blutprodukten. / Background: The physical characteristics of the intravenous anaesthetic propofol enable to detect its specific emission spectrum with fluorescencespectroscopy. Striving for the goal of an instant Propofol-Online-Monitoring in the optically dense medium blood we developed an experimental setting for the research of the behavoiur of the Propofol-signal in circulation filled with blood products. Material and Methods: The designed circulation model allows a continous turnover of a samplevolume of 140,2 ml in the integrated quartzcuvette under reproducible test conditions. To aim to achieve a steady level of fluorescence of the test-medium circultion is necessary, due to the fact that blood products are showing photochemical bleachingeffects in a static setting under the used excitation-wavelenght (UV-C). The used test-mediums are Fresh Frozen Plasma (FFP), a suspension of Erythrocyte Concentrate (EC) and FFP (EC + FFP) plus in a final step a whole blood donation rejected within 12 hours. The testarrangement is starting with the injection of four Propofol-boli, which are diluted to concentrations between 35, 7 μg/ml to 3,6 μg/ml equivalent to clincally relevant levels under anesthetization and while maintaining anaesthesia. With the used exitation wavelength of 274 nm Propofols responses with a maximal signal of emission at 300 nm. With the fluorescence spectrums, detected in short intervalls, follows the analysis of the effect of Propofol at 300 nm in the summation spectrum of the blood-Propofol-mixture. Results: The rises of the fluorescence signal at 300 nm after injection in the circulation-model filled with FFP and EC + FFP are respectively high significant for the generated levels of Propofol between 35, 7 μg/ml to 3,6 μg/ml and show a very good linear correlation between fluorescence signal an concentration of Propofol. These test-mediums are reaching an adaquate signal of fluorescence for the detection of Propofol. After fluorescence rises by addition of Propofol follows a constantly decrease of the signal about 30 minutes. One responsible factor for the drecrease ist he adsorption of the lipophilic anesthetic at silicone tubing in the circulation model. Conclusion: The successfull instant detection of clinically used Propofol levels with a fluorescence signal at 300 nm in dependance on concentration succeeds with transfusion medically treated blood products. The following decrease of fluorescence does not describe pharmacological kinetics of Propofol in blood, because the verifiable adsorption of Propofol at silicone tubings restricts the validity of the in-vitro-model.

Resumo: O estudo teve por objetivo avaliar o índice bispectral, efeitos hemodinâmicos e respiratórios da infusão contínua de diferentes taxas de propofol em bezerros. Foram utilizados 8 animais de seis a 12 meses de idade, holandeses, pesando de 84 a 124 kg. Os animais foram induzidos à anestesia com propofol na dose de 5 mg/kg IV e posicionados em decúbito lateral direito, onde permaneceram respirando espontaneamente ar ambiente. Ato contínuo, a manutenção anestésica foi realizada pela infusão contínua de propofol, administrado por meio de bomba de infusão em duas diferentes taxas 0,6 mg/kg/minuto IV (G06) e 0,8 mg/kg/minuto IV, (G08) durante 60 minutos. Os 8 animais foram anestesiados duas vezes, com uma semana de intervalo entre uma anestesia e outra. As variáveis hemodinâmicas (FC, PAS, PAD, PAM, DC, PVC, PAPm, PAPOm, IC, IS, IRVS e IRVP), respiratórias (ETCO, f, SpO, 2 2 V, V, e PFI), hemogasométricas (PaO, PaCO, SaO, DB, pH e HCO -) e TE ME 2 2 2 3 índice bispectral (BIS, EMG e IQS) foram avaliadas antes da indução anestésica (M ), e 15, 30, 45 e 60 minutos após o início da infusão contínua do B propofol (M15, M30, M45 e M60, respectivamente). Já a colheita das amostras para a dosagem plasmática do propofol foi realizada aos M15, M30, M45 e M60 minutos durante a infusão contínua do propofol e as demais colheitas foram realizadas após o termino da infusão com intervalos de 10 minutos por um período de 50 minutos (M70, M80, M90, M100 e M110 respectivamente). A infusão contínua de diferentes taxas de propofol não alterou as variáveis do BIS ao longo do tempo durante a infusão, também não causou alterações hemodinâmicas importantes, porém o G08 apresentou acidose respiratória indicando uso de ventilação controlada / Abstract: The aim of this study was to evaluate the bispectral index, hemodynamic and respiratory effects of continuous infusion of different rates of propofol in calves. Eight Holstein calves aging between six and 12 months and weighing 84-124 kg were used. They were induced to anesthesia with propofol at a dose of 5 mg / kg IV and positioned in right lateral recumbency, where they remained spontaneously breathing ambient air. Immediately thereafter, the anesthesia was maintained by continuous infusion of propofol administered with the aid of an infusion pump in two different rates 0.6 mg / kg / minute, IV (G06) and 0.8 mg / kg / minute, IV, (G08), during 60 minutes. The 8 animals were anesthetized twice, with one-week interval between anesthesia. The measurements of hemodynamic (HR, SAP, DAP, MAP, CO, CVP, mPAP, mPAPO, CI, SI, SVRI and PVRI), and respiratory parameters (ETCO2, f, SpO2, VTE, VME, and PFI), arterial blood gases (PaO2, PaCO2, SaO2, BE, pH and HCO3-) and bispectral index (BIS, EMG and SQI) were assessed before induction of anesthesia (MB), and 15, 30, 45 and 60 minutes after the start of continuous infusion of propofol (M15 , M30, M45 and M60, respectively). Sampling to measure plasma propofol was performed M15, M30, M45 and M60 minutes during continuous infusion of propofol and other samples were harvested after the end of infusion with 10-minute intervals during a period of 50 minutes (M70, M80, M90, M100 and M110 respectively). Continuous infusion of propofol at different rates did not alter the variables BIS over time and also did not cause significant hemodynamic changes, but the G08 had respiratory acidosis suggesting the use of controlled ventilation / Orientador: Paulo Sergio Patto dos Santos / Banca: Valéria Nobre Leal de Souza Oliva / Banca: Simone Bopp / Mestre

Orientador: Newton Nunes / Coorientador: Patricia Cristina Ferro Lopes / Banca: Roberta Carareto / Banca: Vivian Fernanda Barbosa / Banc: Bruno Watanabe Minto / Resumo: Compararam-se os efeitos de diferentes frações inspiradas de oxigênio (FiO2) associado ao óxido nitroso (N2O) ou ao ar comprimido sobre a hematose, parâmetros cardiorrespiratórios, intracranianos e o índice biespectral (BIS), em leitões mantidos em ventilação espontânea ou controlada a pressão, associada ou não à PEEP (5 cmH2O). Foram utilizados 48 leitões, distribuídos em 6 grupos, submetidos à 10, 30 e 50% de ar comprimido (GA10, GA30 e GA50) ou N2O (GN10, GN30 e GN50), associadas às FiO2 de 0,9, 0,7 e 0,5, respectivamente. O GA30 mostrou maior proximidade do intervalo fisiológico da pressão parcial de oxigênio no sangue arterial. A PEEP não foi eficaz na pressão parcial de dióxido de carbono no sangue arterial, independente da FiO2, quando se utilizou o N2O. O pH, déficit base e bicarbonato no sangue arterial foram influenciados pela FiO2 e N2O. As alterações do volume corrente e volume minuto parecem correlacionadas à introdução da ventilação mecânica (VM) e PEEP. Na diferença alvéolo-arterial de oxigênio, a PEEP influenciou negativamente o GA30 e GN30 e não foi adequada para manutenção do shunt pulmonar. Já a pressão média da artéria pulmonar e pressão média capilar pulmonar apresentaram acréscimos após introdução da PEEP. A associação da PEEP com N2O (50%) ou ar comprimido (50%) parece ser a receita para desempenho inferior da variação de pressão de pulso. Para a pressão intracraniana, apenas o GN30 apresentou valor menor ao se instituir a VM quando comparado com o mome... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The effects of different fractions of inspired oxygen (FiO2) associated with compressed air or nitrous oxide (N2O) on lung oxygenation, cardiorespiratory parameters, intracranial parameters and the bispectral index (BIS) were compared in piglets maintained under spontaneous or controlled ventilation, with or without PEEP (5 cmH2O). Forty-eight piglets, distributed in six groups, were submitted to 10, 30 and 50% of compressed air (GA10, GA30 and GA50) or N2O (GN10, GN30 and GN50), associated with FiO2 of 0.9, 0.7 and 0.5, respectively. GA30 showed greater proximity to the physiological range of partial oxygen pressure in the arterial blood. When N2O was used, PEEP was ineffective in maintaining partial carbon dioxide pressure in the arterial blood, independent of FiO2. Arterial blood pH, base deficit and bicarbonate were influenced by FiO2 and N2O. Changes in tidal and minute volumes seem to correlate with the introduction of mechanical ventilation (MV) and PEEP. The difference in alveolar-arterial oxygen under PEEP negatively influenced GA30 and GN30 and was inadequate for pulmonary shunt maintenance. Mean pulmonary artery pressure and mean capillary pulmonary pressure increased following the initiation of PEEP. The association of PEEP with N2O (50%) or compressed air (50%) seems to result in lower performance of pulse pressure variation. Regarding intracranial pressure, only GN30 presented a lower value when MV was established compared with the time point when PEEP was initi... (Complete abstract click electronic access below) / Doutor

Le but de ce travail était de développer une méthodologie de quantification de la microviscosité membranaire en se basant sur la technique de résonance paramagnétique électronique (RPE) associée au marquage de spin. La méthode a consisté à étalonner les spectres RPE dacides doxylstéariques présentant un groupement nitroxyle à différentes positions de leur chaîne hydrocarbonée dans des mélanges de glycérol/éthanol de viscosité connue. Des courbes étalons, reliant la viscosité au temps de corrélation (τc) et au paramètre dordre (S), ont ainsi été établies. Elles ont, ensuite, été utilisées pour létude de plusieurs systèmes membranaires (micelle, liposome, cellule). En premier lieu, la valeur de la viscosité locale au sein des micelles de détergents synthétiques (SDS, DTAB et CTAB) a été mesurée. Lévolution de cette microviscosité en fonction de la concentration en détergent a permis de donner une approche du phénomène dagrégation de ces micelles. De la même manière, les micelles de deux sels biliaires, le taurocholate et le taurodeoxycholate de sodium, ont été étudiées. Ces dernières présentent un corps micellaire beaucoup plus visqueux que leur région interfaciale hydrophile. En second lieu, la microviscosité à différentes profondeurs dans la bicouche lipidique des liposomes de DMPC a pu être quantifiée. Elle diminue en allant de la surface hydrophile vers le centre hydrophobe de la bicouche. Les effets de la température, du cholestérol et du propofol (PPF), agent hypnotique utilisé en anesthésie générale, sur la fluidité de la bicouche ont aussi été étudiés. Lincorporation du cholestérol dans la bicouche lipidique la stabilise et atténue, voire fait disparaître, la transition de phase. En revanche, le propofol fluidifie la bicouche lipidique. La technique de mesure de la microviscosité par RPE ne permet de mettre en évidence la fluidification quaux fortes concentrations en PPF (≥10-4 mol dm-3). La spectroscopie dabsorption de la mérocyanine 540 (MC540) a permis de montrer qualitativement que leffet existe également aux plus faibles concentrations en PPF (10-7 - 10-6 mol dm-3) qui correspondent aux concentrations atteintes en clinique. Leffet du PPF dans une de ces formulations commerciales Diprivan® sur la fluidité du DMPC na pas pu être étudié en raison de la présence de vésicules dintralipide dans sa composition. Ces vésicules perturbent à la fois les mesures RPE et celles dabsorption. Enfin, la microviscosité des membranes dérythrocytes et de cellules neuronales (Neuro-2a) a pu être quantifiée. A la température physiologique (37°C), la valeur de la microviscosité au centre de la membrane avoisine les 100 cP. Le PPF fluidifie les membranes cellulaires surtout au niveau de la surface de la bicouche lipidique. Cet effet est observable à partir dune concentration en PPF de 10-4 mol dm-3 dans les membranes des érythrocytes, et dès une concentration de 10-5 mol dm-3 dans les membranes des cellules Neuro-2a.